At present there are few breast cancer prevention strategy options for the estimated 25% of post- menopausal women who take hormone replacement for relief of perimenopausal symptoms, other than to discontinue their use of hormones. For many, even women at high risk for development of breast cancer, discontinuing hormone use may mean a dramatic reduction in their quality of life. The majority of estradiol in the breast in post-menopausal women is derived from local production, with the aromatase enzyme responsible for much of the local conversion of androgens to estradiol. Given the biologic significance of proliferation in neoplastic development, and the association between proliferation reduction and clinical benefit in breast cancer treatment trials, we tested the concept of an aromatase inhibitor for chemoprevention in high-risk post-menopausal women on chronic hormone replacement therapy in a single arm pilot study, in which reduction in the proliferation marker Ki-67 was the primary endpoint. Benign breast tissue was obtained by random periareolar fine needle aspiration (RPFNA) at baseline and again after six months of treatment with the aromatase inhibitor letrozole. We observed an average 2.5% reduction in Ki-67 expression despite continuation of hormone replacement during letrozole treatment. Despite dramatic reductions in breast Ki-67 there was little change in perimenopausal symptoms. We now wish to formally test this strategy in a randomized, placebo-controlled multi-institutional Phase II trial. Our primary aim is to determine if six months of letrozole will reduce Ki-67 in hyperplastic tissue in women on estrogen or estrogen plus progestin replacement therapy relative to placebo. Important secondary aims are to determine if letrozole favorably modulates other risk biomarkers such as mammographic density and serum bioavailable estradiol and testosterone; and/or worsens symptoms and quality of life in women on estrogen replacement therapy. If the strategy of addition of an aromatase inhibitor to concomitant estrogen replacement therapy can be validated, it has the potential to impact millions of post-menopausal women, providing the health advantages of estrogen replacement therapy while avoiding an increase in risk for development of breast cancer. [unreadable] [unreadable] [unreadable]